Bioequivalence of a new liquid formulation of ursodeoxycholic acid (Ursofalk suspension) and Ursofalk capsules measured by plasma pharmacokinetics and biliary enrichment.

BACKGROUND: Ursodeoxycholic acid is an approved therapy for hepatobiliary disorders but in infants and children compliance is compromised because it is formulated exclusively as capsules, or tablets. AIM: To determine the pharmacokinetics and bioequivalence of a new liquid formulation of ursodeoxycholic acid (Ursofalk suspension) with a standard capsule (Ursofalk) in a randomized, unblinded, crossover designed study of 24 healthy adults. METHODS: Equivalence was based on single bolus oral plasma pharmacokinetics and biliary ursodeoxycholic acid enrichments after repeat doses. Biliary bile acid composition and hydrophobicity index were also compared. Ursodeoxycholic acid was measured in duodenal bile by high-performance liquid chromatography and in plasma by mass spectrometry. RESULTS: The mean percentage biliary ursodeoxycholic acid enrichment after administration of the suspension was not significantly different from that obtained with capsules (44.2 +/- 11.7% vs. 46.9 +/- 10.2%, respectively). The equivalence ratio was 0.94 (95% CI: 0.8-1.1), establishing bioequivalence between suspension and capsules. Both formulations reduced the biliary hydrophobicity index and no differences in bile acid composition were observed between formulations. The plasma pharmacokinetics of both formulations was similar and the tolerability of the suspension was excellent. CONCLUSIONS: A new liquid formulation of ursodeoxycholic acid suitable for paediatric patients is pharmacologically bioequivalent to capsules when given as single, or repeated oral doses.

Ursodeoxycholic acid increases the activities of alkaline sphingomyelinase and caspase-3 in the rat colon.

BACKGROUND: Ursodeoxycholic acid (UDCA) has been found to inhibit the development of colon carcinoma induced by chemical carcinogens with unidentified mechanisms. Sphingomyelin metabolism has emerged as a novel signal transduction pathway closely related to cell proliferation and apoptosis. We recently found that alkaline sphingomyelinase (SMase) activity was decreased in human colon cancer. The present study is to investigate whether UDCA has effect on the levels of SMase and whether the activity of caspase-3, a key regulatory protease in apoptosis that can be activated by sphingomyelin breakdown products, is also influenced by UDCA. METHODS: Rats were fed UDCA in amounts ranging from 37.5 to 300 mg/kg/day for 10 days by gavage. The colonic mucosa was scraped, homogenized, and sonicated. The activities of acid, neutral and alkaline SMases, and caspase-3 were determined. RESULTS: UDCA dose-dependently increased alkaline SMase activity in colonic mucosa and faeces, slightly increased acid SMase activity in the mucosa, and had no effect on neutral SMase. UDCA also dose-dependently increased caspase-3 activity in the colonic mucosa, and the increase correlated significantly with the changes in alkaline but not that in acid or neutral SMase activity. CONCLUSIONS: UDCA increases alkaline sphingomyelinase and caspase-3 activities, which might be a mechanism involved in its anticarcinogenic effect on colon cancer development.

Effects of ursodeoxycholate and other bile salts on levels of rat intestinal alkaline sphingomyelinase: a potential implication in tumorigenesis.

Previous studies showed that bile salts had a promoting effect on colon cancer development and this effect was inhibited by ursodeoxycholate (UDC). We recently found that both human colorectal adenomas and carcinomas were associated with a specific decrease in alkaline sphingomyelinase activity. In this work, we compared the effects of ursodeoxycholate and other bile salts on the levels of rat intestinal alkaline sphingomyelinase both in the intestinal loops and after oral administration. Bile salts at different concentrations were injected into intestinal loops and the dissociation of alkaline sphingomyelinase from the mucosa was assayed. We found that bile salts, including taurocholate, taurodeoxycholate, glycocholate, glycochenodeoxycholate, and 3-(3-cholamidopropyl dimethylammonio)-1-propanesulonate (CHAPS), dose dependently dissociated alkaline sphingomyelinase from the intestinal mucosa. UDC alone did not dissociate the enzyme but significantly inhibited the dissociation caused by other bile salts and CHAPS. Feeding rats with 0.3% (w/w) taurocholate for four days decreased peak activity of intestinal alkaline sphingomyelinase by 39% and total activity in the intestine by 20% and increased the output of the enzyme in the feces. In contrast, feeding 0.3% (w/w) UDC for four days increased the peak activity of alkaline sphingomyelinase in the small intestine by 87% and the activity in the colon by 187%. The total activity of alkaline sphingomyelinase was increased by 80% and the output of the enzyme in the feces was only slightly increased by UDC administration. The changes in alkaline phosphatase after feeding taurocholate and UDC were much smaller. Our results indicate that UDC and other bile salts have different effects on the levels of alkaline sphingomyelinase, which may be implicated in their different influences on cancer development reported previously.

ATPase and cytochrome oxidase activities at the polar organelle in swarm cells of Sphaerotilus natans: an ultrastructural study.

The polar organelle of bacteria presumably is part of the flagellar apparatus. In order to characterize this structure, cytochemical studies on Sphaerotilus natans have been performed. Marked ATPase activity is associated with the inner boundary layer and central layer of this organelle. The spaces between the boundary layers and the central layer of the polar organelle which are traversed by fine fibrilles are positive for reactions with diaminobenzidine. This indicates cytochrome oxidase activity. S. natans possesses a ribbon-like, helically shaped polar organelle which is divided concomitantly with cell fission, possibly explaining inheritance of this structure and of the flagellar apparatus.

[The percutaneous effect of a heparin-allantoin-dexpanthenol combination in a specific ointment base. Anti-allergic, anti-inflammatory effect in the PCA test in the rat]. / Untersuchungen zur perkutanen Wirksamkeit einer Heparin-Allantoin-Dexpanthenol-Kombination in spezieller Salbengrundlage. Antiallergische/antiinflammatorische Wirkung im PCA-Test bei der Ratte.

Local application of a heparin-allantoin-dexpanthenol (Hepathrombin-Adenylchemie) ointment to rats 15 min prior to induction of a passive cutaneous anaphylaxis (PCA) reaction inhibits the anaphylactic reaction as compared to the ointment base. Also, the Evans Blue content as a measure for vascular permeability and the oedema weights are reduced under the heparin containing ointment. The antiallergic/antiinflammatory effect is probably due to heparin.

[The percutaneous action of a heparin-allantoin-dexpanthenol combination in a specific ointment base. Thrombolytic action on the rabbit ear]. / Untersuchungen zur perkutanen Wirksamkeit von Heparin-Allantoin-Dexpanthenol-Kombinationen in spezieller Salbengrundlage. Thrombolytische Wirkung am Hasenohr.

Experimentally induced thrombi of ear veins in albino rabbits have been treated locally with heparin-containing ointments in presence or absence of allantoin and dexpanthenol, the heparin concentration varying. While the ointments, containing heparin only, induce no or only minor thrombolytic activity, the combination ointments Hepathrombin Adenylchemie containing heparin, allantoin and dexpanthenol show significant thrombolytic activity. This effect is dependent upon the heparin concentration, yet, heparin doses above 50 000 IU per 100 g of ointment do not enhance the thrombolysis furthermore. Further, the studies show that the effective components of Hepathrombin do penetrate into and through the skin, allantoin and dexpanthenol being important components of the ointment probably supporting the transdermal penetration of heparin. The studies also demonstrate the only local thrombolytic effect of the Hepathrombin ointments because the thrombus of the right ear, always treated with ointment base only, did not show any change in length as contrasted to that of the left ear of the same animal treated with the Hepathrombin ointments. Mechanisms of the locally by Hepathrombin/heparin induced thrombolysis will be discussed.

[Investigations on the percutaneous activity of a combination of heparin, allantoin and dexpanthenol in a specific ointment base, Antiinflammatory effect on UV-erythema in the guinea pig]. / Untersuchungen zur perkutanen Wirksamkeit einer Heparin-Allantoin-Dexpanthenol-Kombination in spezieller Salbengrundlage. Antiinflammatorische Wirkung auf UV-Erytheme am Meerschweinchen.

Compared to the ointment base, the application of a heparin-allantoin-dexpanthenol combination ointment (Hepathrombin ointment) to guinea pigs immediately after as well as 30 and 120 min prior to UV-irradiation effects more rapid regression of the erythema along with a reduction in erythema formation. After a pretreatment of 30 min, the temperature of the erythematous skin is also significantly lower. At a pretreatment of 120 min, no temperature differences can be observed between the ointment groups. This effect might result from a superimposition of the anti-erythematous/antiinflammatory effect of Hepathrombin along with a vasodilation effect on the deeper skin layers. The antiinflammatory effect of Hepathrombin is also discussed in connection with the mechanism of UV-induced erythema. The inhibition of UV-erythema by Hepathrombin underlines the rapid skin penetration of the active substances.

[Method for direct measurement of choleresis and secretory function of the exocrine pancreaas demonstrated by sodium dehydrocholate and secretin (author's transl)]. / Methode zur Direktmessung der Cholerese und des Funktionszustandes des exokrinen Pankreas, demonstriert mit Na-Dehydrocholat und Sekretin als Testsubstanzen

A method has been described that enables to check secretory processes in animals directly. This has been demonstrated in dog exocrine pancreas stimulated by secretin and on bile secretion induced by sodium dehydrocholate. The design of this method permits to run experiments on pancreas and choleresis separately as well as simultaneously. The directly recorded absorption curves are in good agreement with the data obtained from the collected fractions. Based on the optical density curves, it is possible to determine the contents of the fractions more directly and more specifically. It is also possible to study kinetic problems and time dependent reactions by using this method and this design.

[Pharmacological effects of piprozoline on bile secretion in dogs (author's transl)]. / Pharmakologische Wirkung von Piprozolin auf die Gallensekretion beim Hund

Ethyl (Z)-(3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)-acetate (piprozoline, Gö 919, Probilin) and its main metabolite Gö 3284 induce a strong choleretic effect in dogs after i.v. and i.d. administration as well. Intestinal absorption is fast, and already 3.5 min after administration of the substances a rise of the bile volume and of the optical density of the secreted bile can be observed. The secretion rates of bile solids and bile acids per time (min) increase almost at the same time, too. Moreover, piprozoline presumably stimulates the synthesis of bile acids and of the other matter in addition to the raised secretory rate. In the group of choleretics, piprozoline is to be placed among the cholepoietics. Under the influence of piprozoline and Gö 3284, the content of solids sometimes decreases for a short period immediately after administration of substances. A strong linear correlation occurs between the secretion rate of bilirubin and bile acids. The increase of bile volume under the influence of piprozoline and Gö 3284 may be seen as osmotic effects caused by the stimulation of the bile acid dependent and the bile acid independent (Na+-ion dependent) canalicular mechanisms of choleresis.

[Pharmacological effect of piprozoline on the exocrine pancreas of dogs (author's transl)]. / Pharmakologische Wirkung von Piprozolin auf das exokrine Pankreas beim Hund

Ethyl (Z)-(3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)-acetate (piprozoline, Gö 919, Probilin) and its main metabolite Gö 3284 cause a long-acting stimulation of the ecbolic function of the exocrine pancreas in the dog after intraduodenal administration or after i.v. injection. This has been demonstrated by canulation of the ductus pancreaticus accessorius and by perfusion of the small bowel as well as by photometric evaluation of the perfusion streams and determinations of the activities of alpha-amylase, lipase and trypsin in the 2-min fractions thereafter. Piprozoline does not cause a rise of the bicarbonate secretion and volume. In its action to the exocrine pancreas it resembles very much cholecystokinin-pancreozymin. The value of piprozoline is discussed with regard to its stimulating effect on the ontogenetic unit of the epigastric region.